Quantitative differences in gene expression are thought to contribute to phenotypic differences between individuals. We generated genome-wide transcriptional profiles of lymphocyte samples from 1,240 participants in the San Antonio Family Heart Study. The expression levels of 85% of the 19,648 detected autosomal transcripts were significantly heritable. Linkage analysis uncovered >1,000 cis-regulated transcripts at a false discovery rate of 5% and showed that the expression quantitative trait loci with the most significant linkage evidence are often located at the structural locus of a given transcript. To highlight the usefulness of this much-enlarged map of cis-regulated transcripts for the discovery of genes that influence complex traits in humans, as an example we selected high-density lipoprotein cholesterol concentration as a phenotype of clinical importance, and identified the cis-regulated vanin 1 (VNN1) gene as harboring sequence variants that influence high-density lipoprotein cholesterol concentrations.

BACKGROUND The Long QT Syndrome (LQTS) is an infrequently occurring familial disorder in which affected individuals have electrocardiographic QT interval prolongation and a propensity to ventricular tachyarrhythmic syncope and sudden death. We prospectively investigated the clinical characteristics and the long-term course of 3,343 individuals from 328 families in which one or more members were identified as affected with LQTS (QTc greater than 0.44 sec1/2). METHODS AND RESULTS The first member of a family to be identified with LQTS, the proband, was usually brought to medical attention because of a syncopal episode during childhood or teenage years. Probands (n = 328) were younger at first contact (age 21 +/- 15 years), more likely to be female (69%), and had a higher frequency of preenrollment syncope or cardiac arrest with resuscitation (80%), congenital deafness (7%), a resting heart rate less than 60 beats/min (31%), QTc greater than or equal to 0.50 sec1/2 (52%), and a history of ventricular tachyarrhythmia (47%) than other affected (n = 688) and unaffected (n = 1,004) family members. Arrhythmogenic syncope often occurred in association with acute physical, emotional, or auditory arousal. The syncopal episodes were frequently misinterpreted as a seizure disorder. By age 12 years, 50% of the probands had experienced at least one syncopal episode or death. The rates of postenrollment syncope (one or more episodes) and probable LQTS-related death (before age 50 years) for probands (n = 235; average follow-up 54 months per patient) were 5.0% per year and 0.9% per year, respectively; these event rates were considerably higher than those observed among affected and unaffected family members. CONCLUSIONS Among 232 probands and 1,264 family members with prospective follow-up, three factors made significant independent contributions to the risk of subsequent syncope or probable LQTS-related death before age 50 years, whichever occurred first (Cox hazard ratio; 95% confidence limits): 1) QTc (1.052; 1.017, 1.088), 2) history of cardiac event (3.1; 1.3, 7.2), and 3) heart rate (1.017; 1.004, 1.031). The findings from this prospective longitudinal study highlight the clinical features, risk factors, and course of LQTS.

To the Editor: We would like to announce the availability of our package, Programs for Pedigree Analysis. The first program in the package, MENDEL, is intended for gene mapping calculations, genetic counseling, segregation analysis, paternity testing, and related kinds of problems. The second program, FISHER, is designed for the analysis of classical biometric traits like blood pressure and total finger ridge count. The third program, dGENE, serves as an interface to the popular microcomputer data base management system dBASE 111. Our documentation shows how to set up a genetic data base using dBASE 111. dGENE can then be used to extract information from this data base in the correct format for input to the analysis programs MENDEL and FISHER. MENDEL and FISHER are written in FORTRAN 77; dGENE is written in the dBASE 111 programming language. At this time the program SEARCH described in John Hopper's review is not being distributed.The bulk of MENDEL and FISHER will be supplied as object code. dGENE will be supplied as executable code for IBM PCs and compatibles. Source code is available in MENDEL to permit users to modify subroutines defining penetrances, prior probabilities of genotypes, and transmission probabilities from parental genotypes to gamete genotypes. In FISHER the source code defining trait means, variances, and covariances can likewise be modified. There are also subroutines for changing the likelihood of individual pedigrees, defining parameter specifications, and increasing program array dimensions. Both programs can be run in either interactive or batch mode. Full documentation is provided. This includes definition of all variables and a detailed description of the subroutines.MENDEL has a number of attractive features. For instance, phenotype data can be character and need not be translated into integers. Unobserved phenotypes are coded as blanks. MENDEL incorporates an algorithm for automatic elimination of superfluous genotypes of an individual based on the phenotypes of surrounding pedigree members. Correct handling of inbreeding and other loops is done internally by MENDEL, and there is no need for users to split complicated pedigrees. Mono-

These results highlight the importance of considering genetic factors in studies of risk factors for cardiovascular disease.

Chronic inflammation has a pathological role in many common diseases and is influenced by both genetic and environmental factors. Here we assess the role of genetic variation in selenoprotein S (SEPS1, also called SELS or SELENOS), a gene involved in stress response in the endoplasmic reticulum and inflammation control. After resequencing SEPS1, we genotyped 13 SNPs in 522 individuals from 92 families. As inflammation biomarkers, we measured plasma levels of IL-6, IL-1beta and TNF-alpha. Bayesian quantitative trait nucleotide analysis identified associations between SEPS1 polymorphisms and all three proinflammatory cytokines. One promoter variant, -105G --> A, showed strong evidence for an association with each cytokine (multivariate P = 0.0000002). Functional analysis of this polymorphism showed that the A variant significantly impaired SEPS1 expression after exposure to endoplasmic reticulum stress agents (P = 0.00006). Furthermore, suppression of SEPS1 by short interfering RNA in macrophage cells increased the release of IL-6 and TNF-alpha. To investigate further the significance of the observed associations, we genotyped -105G --> A in 419 Mexican American individuals from 23 families for replication. This analysis confirmed a significant association with both TNF-alpha (P = 0.0049) and IL-1beta (P = 0.0101). These results provide a direct mechanistic link between SEPS1 and the production of inflammatory cytokines and suggest that SEPS1 has a role in mediating inflammation.

Obesity is a major predisposing factor for the development of several chronic diseases including non-insulin dependent diabetes mellitus (NIDDM) and coronary heart disease (CHD). Leptin is a serum protein which is secreted by adipocytes and thought to play a role in the regulation of body fat. Leptin levels in humans have been found to be highly correlated with an individual's total adiposity. We performed a genome-wide scan and conducted multipoint linkage analysis using a general pedigree-based variance component approach to identify genes with measurable effects on quantitative variation in leptin levels in Mexican Americans. A microsatellite polymorphism, D2S1788, mapped to chromosome 2p21 (approximately 74 cM from the tip of the short arm) and showed strong evidence of linkage with serum leptin levels with a lod score of 4.95 (P = 9 x 10(-7)). This locus accounted for 47% of the variation in serum leptin levels, with a residual additive genetic component contributing an additional 24%. This region contains several potential candidate genes for obesity, including glucokinase regulatory protein (GCKR) and pro-opiomelanocortin (POMC). Our results show strong evidence of linkage of this region of chromosome 2 with serum leptin levels and indicate that this region could contain an important human obesity gene.

Three separate genetic loci for the long QT syndrome including mutations in two cardiac ionic channel genes were associated with different phenotypic T-wave patterns on the ECG. This study provides insight into the influence of genetic factors on ECG manifestations of ventricular repolarization.

Computer simulation is a valuable tool in the genetic management of captive populations. It can be used to assess the extent of genetic variability in a colony, to predict the risk of future loss of variability, or to identify likely ancestral sources of traits of interest. "Gene dropping"tis a simulation procedure in which hypothetical alleles are assigned to each colon! founder, and a genotype is created for each descendant by Mendelian segregation of parental alleles. The gene dropping method is applied to analyses of four populations: (1) a colony of small South American marsupials, Monodelphis domesticu; (2) Speke's gazelles, Guzella spekei; (3) Przewalski's horses, Equus przewalskii; and (4) American Standardbred horses.